Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection

Circulation
Tzong-Shyuan LeeJohn Y-J Shyy

Abstract

Evidence from experimental and clinical studies indicates that statins can protect the vessel wall through cholesterol-independent mechanisms. The "pleiotropic" effects include the prevention of inflammation and proliferation of vascular cells. Here, we studied whether heme oxygenase-1 (HO-1), an important cytoprotective molecule, is induced by simvastatin and the role of HO-1 in the pleiotropic effects of simvastatin. Human and rat aortic smooth muscle cells treated with simvastatin showed an elevated level of HO-1 for up to 24 hours. The induction of HO-1 by simvastatin was not found in cultured endothelial cells and macrophages. Injecting C57BL/6J mice intraperitoneally with simvastatin increased the level of HO-1 in vascular SMCs (VSMCs) in the tunica media. Treating VSMCs with zinc protoporphyrin, an HO-1 inhibitor, or HO-1 small interfering RNA (siRNA) blocked the antiinflammatory effect of simvastatin, including the inhibition of nuclear factor-kappaB activation and nitric oxide production. Blockade of HO-1 also abolished the simvastatin-induced p21(Waf1) and the associated antiproliferative effect. Simvastatin activated p38 and Akt in VSMCs, and the respective inhibitors of p38 and phosphoinositide 3-kinase (PI3K) great...Continue Reading

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